Diastereo- And Enantioselective Synthesis of Quaternary α-Amino Acid Precursors by Copper-Catalyzed Propargylation

Article abstract of DOI:10.1021/acs.orglett.9b03894

A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is described. This method allows the preparation of a series of non-proteinogenic quaternary α-amino acid precursors featuring two contiguous stereogenic centers and a terminal alkyne moiety in high yields with good to excellent diastereo- and enantioselectivities in most cases. The propargylated adducts were elaborated into a diverse set of quaternary α-amino acid derivatives.

Full text of DOI:10.1021/acs.orglett.9b03894

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereo- and Enantioselective Synthesis of Quaternary α‑Amino
Acid Precursors by Copper-Catalyzed Propargylation
Qiongqiong Zhu,† Beibei Meng,† Congzheng Gu,† Ye Xu,† Jie Chen,† Chuanhu Lei,*,†
and Xiaoyu Wu*,†,‡
†Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, College of Sciences, Shanghai University, 99
Shangda Lu, Shanghai 200444, People’s Republic of China
‡Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: A diastereo- and enantioselective propargylic
substitution reaction between propargylic carbonates and α-
substituted nitroacetates catalyzed by a Cu−pybox complex is
described. This method allows the preparation of a series of
non-proteinogenic quaternary α-amino acid precursors featur-
ing two contiguous stereogenic centers and a terminal alkyne
moiety in high yields with good to excellent diastereo- and
enantioselectivities in most cases. The propargylated adducts
were elaborated into a diverse set of quaternary α-amino acid
derivatives.
Scheme 1. Copper-Catalyzed APS Reaction and Our Design
for the Preparation of Quaternary α-Amino Acids
ecause of the broad reactivity of alkynes, particularly in
Bthe celebrated click reaction, copper-catalyzed azide
alkyne cycloaddition,1 terminal-alkyne-functionalized α-amino
acids have come to play an increasingly important role in
medicinal chemistry and peptide chemistry.2 However, the
asymmetric catalytic synthesis of quaternary α-amino acids
featuring a terminal alkyne moiety has been quite challenging
and remains chemistry that is largely underdeveloped.3 The
design of new asymmetric catalytic reactions between
nucleophilic α-amino acid precursors and electrophiles
containing a terminal alkyne functionality leading to
quaternary α-amino acids could serve to address this current
limitation.4
Over the past few years, copper−allenylidene complexes
generated from terminal alkyne propargylic alcohol derivatives
and Cu-based chiral catalysts have emerged as versatile reactive
species for the design of asymmetric propargylic substitution
(APS) reactions with various nucleophiles, including C-based
nucleophiles and heteroatom-based nucleophiles (Scheme
1).5,6 Despite these achievements, the application of
nucleophilic amino acid precursors to APS reactions remains
an unmet synthetic challenge; indeed, to our knowledge this
chemistry has yet to be reported. The most closely related
examples were very recently reported by Niu and co-workers,
wherein APS reactions of α-thio/α-oxacarboxylic acid
precursors were realized through Cu/Zn or Cu/Ti catalysis.6p
Such types of reactions, if successful, would install a terminal
alkyne function on non-proteinogenic α-amino acids stereo-
selectively. Herein we report a highly efficient Cu-catalyzed
APS of α-substituted nitroacetates7 with tert-butyl propargylic
carbonates, leading to structurally diverse quaternary α-amino
acid precursors bearing a terminal alkyne moiety. Key to this
development is the finding that pybox ligands bearing aryl
groups at the 5-positions of the oxazoline rings allow for robust
catalytic performance.8
Initially, we examined the reaction between tert-butyl
propargyl carbonate 1a and methyl 2-nitro-2-phenylacetate
(2a) promoted by a copper complex generated in situ from
Cu(CH3CN)4BF4 (10 mol %) and (S)-sec-butyl-pybox (L1)
(12 mol %) at −10 °C with dichloromethane as the solvent
and DIPEA as the base (Table 1, entry 1). To our delight, the
reaction proceeded smoothly to afford the desired propargy-
lation product 3aa in high yield (83%), albeit with modest
selectivities. Encouraged by this promising result, a set of other
tridentate pybox ligands derived from commercially available
Received: November 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
that the initial results could not be improved further (data not
shown; see the Supporting Information for details). Switching
the base from DIPEA to N-ethylmorpholine (NEM) (entry
17) in the presence of L12 led to a slight increase (relative to
entry 12) in diastereoseclectivity (2.4:1 to 3.2:1) while
providing almost identical yield and ee values. The reaction
temperature was found to have a readily discernible impact on
the diastereoselectivity. APS reactions carried out at −40 °C
afforded a dr of 7.6:1 with 97% ee for the major
diastereoisomer without affecting the high conversion, albeit
at the expense of longer reaction times (entry 18). Further
lowering the temperature to −50 °C gave a lower yield of 70%
after 96 h. Reducing the loading of both components of the
copper complex as well as the volume of the solvent by 50%
still gave rise to an excellent yield of 3aa without deterioration
of either the dr or ee (entry 20).
Table 1. Optimization of the Reaction Conditions
b
c
d
entry
L
temp (°C)
base
yield (%)
dr
ee (%)
With the optimized reaction conditions established (Table 1,
entry 20), we chose α-phenyl nitroacetate 2a as the model
nucleophile to explore the reaction scope and assess the effect
of different substituents at the propargylic position (Table 2).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
L1
L2
L3
L4
L5
L6
L7
L8
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−40
−50
−40
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
83
78
82
77
78
80
81
trace
90
92
93
95
92
82
81
92
95
94
70
93
2.3:1
3.3:1
1.4:1
1.1:1
1.4:1
3.8:1
1.5:1
−
1.8:1
1.7:1
2.3:1
2.4:1
1.7:1
1.8:1
2.1:1
1.9:1
3.2:1
7.6:1
7.6:1
7.6:1
59
15
65
78
83
40
27
−
85
92
94
95
89
82
90
88
95
97
97
97
a
Table 2. Scope of Terminal Alkyne Propargylic Carbonates
L9
L10
L11
L12
L13
L14
L15
L16
L12
L12
L12
L12
b
c
d
entry
1, R
1a, C6H5
3
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
93
83
84
80
97
93
78
78
83
78
70
71
74
77
7.6:1
4.2:1
5.7:1
5.5:1
8.7:1
20:1
6:1
5.3:1
1.5:1
1.8:1
5.6:1
4.2:1
6.8:1
6.9:1
97
96
97
96
97
97
90
96
1b, 4-ClC6H4
1c, 4-FC6H4
1d, 4-BrC6H4
1e, 4-MeC6H4
1f, 4-MeOC6H4
1g, 2-MeOC6H4
1h, 3-BrC6H4
1i, 1-naphthyl
1j, 2-thienyl
1k, CH3
e
NEM
NEM
NEM
NEM
f
20
a
General conditions: 1a (0.1 mmol), 2a (0.2 mmol), Cu-
(CH3CN)4BF4 (10 mol %), ligand (12 mol %), and DIPEA (2
91 (83)
86 (82)
68
b
equiv) in DCM (1 mL) at 10 °C for 4−24 h. Yields of isolated pure
c
d
3aa. The dr of 3aa was determined by 1H NMR spectroscopy. The
1l, Bn
1m, Et
1n, Bu
92
97
97
e
ee of 3aa was determined by chiral HPLC analysis. NEM = N-
ethylmorpholine. The reaction was performed with 5 mol %
f
Cu(CH3CN)4BF4 and 6 mol % L12 in DCM (0.5 mL).
a
General conditions: 1 (0.1 mmol), 2a (0.2 mmol), Cu-
(CH3CN)4BF4 (5 mol %), ligand (6 mol %), and N-ethylmorpholine
b
amino acids were also evaluated for their ability to promote
this APS reaction (entries 2−7). In all cases, the desired
products were obtained in yields comparable to that with L1.
Interestingly, the highest enantioselectivity (83% ee) was
obtained for ligand L5 bearing less bulky methyl groups,
although the diastereoselectivity was rather low (1.4:1) (entry
5). Indenylpybox ligand L8 was not suitable for this reaction
since no formation of 3aa was observed (entry 8).
Unexpectedly, installing a phenyl substituent at C5 of each
oxazoline ring of the pybox ligand (L9) resulted in an
enhanced reaction rate, allowing for complete conversion in 4
h (90% yield) along with a slight improvement (relative to L5)
in enantioselectivity (entry 9). Further screening of pybox
ligands with different substitution patterns revealed that L12
was the best in terms of both yield and stereoselectivity
(entries 10−16).
(2 equiv) in DCM (0.5 mL) at 40 °C for 48−72 h. Yields of isolated
c
d
pure 3. The dr of 3 was determined by 1H NMR spectroscopy. The
ee’s of the major diastereoisomers were determined by chiral HPLC
analysis; values in parentheses are the ee’s of the minor
diastereoisomers.
To our delight, phenylpropargylic carbonate substrates bearing
various electron-withdrawing or -donating substituents at the
para position of the benzene ring (entries 1−6) all performed
well and afforded phenylglycine derivatives 3aa−fa in good to
excellent yields (80−97%). Synthetically useful diastereose-
lectivities (4.2:1 to 20:1) and excellent enantioselectivities
(96−97% ee) were also seen. Substrates bearing a substituent
at the ortho or meta positions of the benzene ring were also
examined; again, the corresponding products 3ga and 3ha
were obtained readily (entries 7 and 8). The presence of a
bulky 1-naphthyl group did not reduce the efficiency of the
catalysis, although a lower diastereoselectivity was seen (entry
Attempts to improve the performance of the APS reaction
by screening copper salts and solvents proved unsuccessful in
B
DOI: 10.1021/acs.orglett.9b03894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
9). A notably lower enantioselectivity (86% ee) was observed
for 2-thienyl-substituted substrate 1j (entry 10). Alkyl-
substituted precursors 1k, 1m, 1n and benzyl-substituted
precursor 1l, which were prepared from the corresponding
alcohols and perfluorobenzoic chloride, reacted smoothly with
2a to afford the desired products in satisfactory fashion (entries
11−14), although a moderate level of enantioselectivity was
seen in the case of 1k. It is possible that the reduced steric
demands of the methyl substituent in 1k resulted in a less
efficient chiral induction.
products could be used to prepare α-substituted aspartic acid
and glutamic acid, respectively. The scope was further
expanded to p-bromophenyl (1d), p-methylphenyl (1e), and
p-methoxyphenyl (1f) substituted propargylic carbonates
(entries 16−20). Reactions between two alkyl partners, e.g.,
1l + 2k and 1l + 2j, were also tested. Unfortunately, no
formation of the propargylation product was observed.
The nitro ester products could be readily converted to α-
amino carboxylic esters by reduction with zinc in aqueous
HCl/EtOH at room temperature. As shown in Scheme 2, a
Next, the present study was extended to α-substituted
nitroacetates (Table 3). We were pleased to find that
Scheme 2. Reduction of Nitro Esters over Zn/HCl
a
Table 3. Scope of α-Substituted Nitroacetates
b
c
d
entry
1, 2, R
1a, 2a, C6H5
3
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
93
82
75
92
91
88
84
80
86
83
85
94
78
71
88
75
85
84
88
80
7.6:1
4.7:1
2.8:1
6.2:1
6.6:1
2.7:1
4:1
10:1
1.6:1
3.5:1
20:1
3.6:1
2:1
1.7:1
1.9:1
3.6:1
20:1
6.3:1
15:1
20:1
97
96
94
96
97
1a, 2b, 4-FC6H4
1a, 2c, 4-ClC6H4
1a, 2d, 4-MeC6H4
1a, 2e, 4-MeOC6H4
1a, 2f, 3-MeOC6H4
1a, 2g, 2-MeOC6H4
1a, 2h, 1-naphthyl
1a, 2i, CH3
95 (78)
90
89
variety of propargylation adducts could be reduced to the
corresponding amino carboxylic esters in good yields using this
approach. Moreover, the enantioselectivities remained similar
within experimental error for all of the compounds obtained in
this way. On the other hand, a slight decrease in the
diastereoselectivity was observed for most of the substrates,
possibly because of epimerization at the propargylic position.
Other reduction conditions, such as NaBH4/NiCl2 and Zn/
AcOH, were also tested and found to be unsuitable for
promoting this transformation.
88 (85)
84
1a, 2j, CH3CH2
1a, 2k, i-Pr
1a, 2l, n-Bu
3aj
3ak
3al
91
89
1a, 2m, Bn
3am
3an
3ao
3de
3dh
3ee
3ek
3fk
93 (85)
86 (79)
84 (72)
93
1a, 2n, MeO2C(CH2)
1a, 2o, MeO2C(CH2)2
1d, 2e, 4-MeOC6H4
1d, 2h, 1-naphthyl
1e, 2e, 4-MeOC6H4
1e, 2k, i-Pr
83
95
97
90
The absolute stereochemistry of propargylation adduct 3ac
bearing an aromatic substituent at the α-position was
determined to be 2S,3R by chemical correlation after its
transformation to 5ac through reduction with zinc followed by
hydrogenation over Lindlar catalyst (Scheme 3).9 Similarly, the
1f, 2k, i-Pr
a
General conditions: 1 (0.1 mmol), 2 (0.2 mmol), Cu(CH3CN)4BF4
(5 mol %), ligand (6 mol %), and N-ethylmorpholine (2 equiv) in
b
c
DCM (0.5 mL) at 40 °C for 48−72 h. Yields of isolated pure 3. The
d
1
dr of 3 was determined by H NMR spectroscopy. The ee’s of the
major diastereoisomers were determined by chiral HPLC analysis;
values in parentheses are the ee’s of the minor diastereoisomers.
Scheme 3. Derivatization of 3ac and 3ak for Structural
Elucidation
substrates 2b−g, which are precursors to substituted phenyl-
glycines, reacted with 1a smoothly regardless of the electronic
nature of the substituents. These reactions provided the
desired propargylic products in good yields with moderate to
good diastereoselectivities and excellent enantioselectivities
(entries 2−7). A bulky naphthyl substituent was also tolerated
in this reaction (entry 8). Moreover, aliphatically substituted
nitroacetates appeared to be good nucleophiles in this process
(entries 9−15). However, the diastereoselectivity was in
general lower than that seen in the case of the aromatically
substituted nitroacetates, with the isopropyl substituent being
an exception; here a dr of 20:1 was seen (entry 11). A benzyl
substituent was also compatible with the reaction, leading to
3am, which is a precursor for α-substituted phenylalanines
(entry 13). Side chains bearing an ester functional group were
also tolerated (entries 14 and 15), and the propargylation
stereochemistry of 3ak bearing an aliphatic substituent at the
α-position was determined to be 2R,3R.9 Furthermore, the
absolute stereochemistry of 3ah was determined to be 2S,3R
by means of single-crystal X-ray diffraction analysis.10 Stereo-
chemical assignments for the other propargylation products
were then assigned by making correlations to (2S,3R)-3ac,
(2S,3R)-3ah, or (2R,3R)-3ak as appropriate.
C
DOI: 10.1021/acs.orglett.9b03894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The practicality of the current method was further
demonstrated by carrying out a relatively large scale synthesis
of 3aa. Specifically, under optimized conditions, the reaction
between 1a and 2a was carried out on a 1 mmol scale; this gave
the propargylation product 3aa in 90% yield with a dr of 7.5:1
in 96% ee (Scheme 4). Standard postsynthetic functionaliza-
Experimental procedures and spectroscopic data for new
compounds (PDF)
Accession Codes
CCDC 1949829 and 1960014 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Scheme 4. Synthesis of 3aa on a 1 mmol Scale and Its
Further Derivatization
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chlei@shu.edu.cn.
*E-mail: wuxy@shu.edu.cn.
ORCID
Xiaoyu Wu: 0000-0001-7179-4280
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Jonathan L. Sessler (The University of
Texas at Austin and Shanghai University) for kindly proof-
reading the revised version of the manuscript. This work was
supported by the National Natural Science Foundation of
China (21672137 and 21971158).
REFERENCES
■
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03894.
D
DOI: 10.1021/acs.orglett.9b03894
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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DOI: 10.1021/acs.orglett.9b03894
Org. Lett. XXXX, XXX, XXX−XXX